New 1-acyl-1-(2-cyano-ethyl)-2-(5-nitrofurylidene)hydrazines and the preparation thereof



3,043,853 NEW l-ACYL-1-(2-CYANO-ETHYL)-2-(5-NITROFUR-FURYLiDENE)I-IYDRAZINES AND THE PREPA- RATION THEREOF Frank F. Ebetino,Norwich, N.Y., assignor to The Norwich Pharmacal Company, Norwich, N.Y.,a corporation of New York No Drawing. Filed Feb. 23, 1960, Ser. No.10,040 Claims. (Cl. 260-3473) This invention relates to a series of newchemical compounds which -are highly effective chemotherapeutic agentsupon oral administration, the preparation thereof, and a new compoundthat is useful as an intermediate in the preparation of members of mynew series of chemotherapeutic agents. Such series may be characterizedas 1- acyl 1 (2 cyanoethyl) 2 (5 nitrofurfurylidene)- hydrazinecompounds which may be represented by the formula:

CHzOHzCN in which X represents a member of the group consisting of aminoand lower alkyl.

I have discovered that the members of my series of new compounds possessa high order of systemic therapeutic activity when administered to hostsinfected with various pathogenic microorganisms at dosages causing nomanifestation of toxic effect.

Chickens infected with a heavy inoculum of the Eimeria tenella organism,the causative agent of cecal coccidiosis, are protected against theravages of that disease through the administration in their diet of0.011% by weight of my new compounds. Mice lethally challenged withStaphylococcus awreus are spared to the extent of 80% by the peroraladministration post infection of 210 mg./ kg. of members of my series.

My new compounds are relatively nontoxic; a dose of 2200 mg./kg. beingtolerated without ill effect by mice.

The compounding and formulating of my new compounds in dosage formscapable of ready administration is easily accomplished in accordancewith accepted practice in the art. Tablets, suspensions, capsules andlike dosage forms containing my new compounds in desired quantity can bereadily prepared using excipients, adjuvants and carriers conventionallyemployed. In veterinary use the admixture of my new compounds in thefeed or drinking water supply serves to provide an ingestible dosageform.

The new chemical compound which I have found to be a valuable syntheticintermediate in the preparation of members of my series isS-nitrofurfurylidene 2-cyanoethyl hydrazone.

It is a particular feature of my invention that my new 1 acyl 1 (2cyanoethyl) 2 (5 nitrofurfurylidene)hydrazine compounds can be preparedin a facile manner from a readily available starting compound, namely,Z-cyanoethylhydrazine:

(1) In the preparation of my new l-alkanoyl-l-(Z- cyanoethyl) 2 (5nitrofurfurylidene)hydrazine compounds, that starting compound iscondensed with 5- nitrofurfural to yieldS-nitrofurfurylidene-2-cyanoethylhydrazone which is .acylated bysubjecting it to treatment with an alkanoic acid anhydride under theinfluence of heat to produce the desired end product; or the startingcompound, 2-cyanoethylhydrazine, is condensed with a suitable carbonylcompound such as acetone or benzaldehyde and the hydrazone thus obtainedis subjected to acylation to produce an intermediate which is subjectedto carbonyl compound exchange with S-nitrofurfural.

(2) The 1 carbamyl 1 (2 cyanoethyl) 2 (5- 3,043,853 Patented July 10,1962 'nitrofurfurylidene)hydrazine that I have invented can be EXAMPLE I1 -A cetyl-I (Z-Cyanoethyl) -2-(5-Nitr0-2-Furfurylidene)Hydrazine 1 31g. (0.389 mole) of S-nitrofurfurylidene Z-cyanoethylhydrazone (M.P.132133), prepared by condensing S-nitrofurfural with2-cyanoethylhydrazine in a manner customary for such condensation, andml. of acetic anhydride are heated at reflux for 15 minutes. The darksolution is cooled in an ice bath, and the precipitated orange-red solidfiltered and slurried with ethanol and again filtered. The dried solidweighs 82 g.; M.P. 185.5- 188. The crude solid may be recrystallizedfrom a mixture of 300 ml. of n-itromethane and 450 ml. of ethanol,clarified with charcoal, and rinsed with a mixture of 30 ml. ofnitromethane and 60 ml. of ethanol. The yield of orange solid,1-acetyl-1-(2-cyanoethyl)-2-(5-nitro-2- furfurylidene)hydrazine, is 70g. (72%) M.P. l88l90.

EXAMPLE II 1 -B wtyry l l (Z-Cyanoethyl -2- (5 -Nitrofurfurylidene)Hydrazine 81 g. (0.389 mole) of S-nitrofurfurylideneZ-cyanoethylhydrazone is treated with ml. of butyric anhydride and 8 ml.of pyridine, and heated at 125-135" until a yellow solid separates oncooling the reaction mixture. The reaction is then further cooled in anice bath, the yellow-orange solid filtered and washed twice withethanol. The yield is 71 g. of l-butyryl-l-(2-cyanoethyl)-2-(S-nitrofurfurylidene)hydrazine (65.6%) M.P. 129- 131". It may berecrystallized from 1200 ml. of isopropanol to give 66 g. M.P. 131132.

EXAMPLE III 1 -Carbamyl-1 Z-Cyanoethyl -2- (5 -N itrofurfunylidene)Hydrazine To asolution of 8.1 g. of potassium cyanate dissolved in 100ml. of water is added 13.4 g. of 2-cyanoethylhydrazine sulfate inportions while maintaining a pH of about 66.5. After addition thesolution is further acidified with hydrochloric acid. To it is added,with stirring, a solution of 14.1 g. of S-nitrofurfural in 100 ml. ofethanol. After a brief induction period a solid is deposited which isfiltered, washed well with alcohol and water and finally dried. Thereare obtained 6.5 g. (25%) of l-carbamyl 1 (2 cyanoethyl) 2 (5nitrofurfurylidene)- hydrazine; M.P. 223-226". It may be recrystallizedwith nitromethane.

What I claim is:

1. A compound having chemotherapeutic activity upon oral administrationand represented by the formula:

climonioN oiN oH=N-N-o 0-1:

in which X represents a member of the group consisting of amino andlower alkyl.

d 2. The compound l-carbamyl-1-(2-cyanoethyl)-2-(5-nitrofurfurylidene)hydrazine represented by the formula:

i onzomon 10 om o 'oH=N-N-oo-on 4. The compoundl-bntyryl-l-(Z-cyanoethyl)-2-(5-ni-' trofurfurylidenemydrazinerepresented by the formula:

1 c nnamon om O CH=N-N-f(JQ-CH1OH2OH,

page 210.

4 r 5. The compound S-nitrofurfurylidene Z-cyanoethylhydrazonerepresented by the formula:

O2NlOlCH=NNHCHzCH2CN References Cited in the file of this patent UNITEDSTATES PATENTS Stillman et al Feb. 18, 1947 Stillman et a1. Feb. 18,1947 OTHER REFERENCES Karrer: Organic Chemistry (2nd English ed., 1946),

Whitmore: Organic Chemistry (D. 'Van Nostrand, sec- 0nd edition, 1951),pp. 292-293, 299 and 450.

1. A COMPOUND HAVING CHEMOTHERAPEUTIC ACTIVITY UPON ORAL ADMINISTRATIONAND REPRESENTED BY THE FORMULA: